The overall aim of my laboratory is to better understand the cellular and molecular underpinnings of the ontogeny of the mammalian hematopoietic system. The parent grant ("Initiation of embryonic hematopoiesis") is focused on the investigation of the origin of [unreadable] hematopoiesis in the mouse embryo and mouse embryonic stem (ES) cells cultured as embryoid bodies. During the initial funding period of the parent grant, we determined that two distinct "primitive" and "definitive" waves of hematopoietic progenitors arise in the yolk sac of the mouse embryo. In the first aim of the parent grant we obtained evidence in both mouse embryos and murine embryoid bodies that megakaryocyte progenitors arise in association with the primitive wave of hematopoiesis. In Aim 1 of this supplement, we will determine the origin of the human megakaryocyte lineage and characterize its relationship to the erythroid progenitors that emerge from embryoid bodies derived from human ES02 cells (ESI). The close association of primitive red cells and endothelial cells in yolk sac blood islands led to the concept of a common hemangioblast precursor for the hematopoietic and endothelial lineages. Evidence for such a precursor has been most convincingly obtained from murine embryoid bodies and in the second aim of the parent grant we are characterizing hemangioblast emergence in the mouse embryo. We will extend these studies of hemangioblast development from the mouse to the human in Aim 2 of this supplement. Our underlying hypothesis is that human ES cell-derived embryoid bodies can serve as an important model system for understanding early embryonic lineage commitment. By understanding these events, the promise of providing tissues for therapeutic regeneration of damaged and diseased organs can ultimately be achieved. Furthermore, a better understanding of the initiation of mammalian hematopoiesis will provide insights into the origin of hematopoietic stem cells and the development of leukemias and marrow failure syndromes. [unreadable] [unreadable] [unreadable]